DESCRIPTION (From the Applicant's Abstract): Glycosphingolipids (GSLs) are enriched in plasma membranes and comprise the gangliosides and the neutral glycosphingolipids. The infantile and juvenile forms of the ganglioside storage diseases (GM1 and GM2 gangliosidoses) present with severe mental and motor degeneration within the first few years of birth due largely to ganglioside accumulation in the brain. Since complex GSLs are actively synthesized during early stages of mammalian embryonic development, neuropathology associated with ganglioside accumulation will commence during fetal development and will worsen in the postnatal brain. An effective treatment strategy would therefore require aggressive early intervention. The objective of this application is to evaluate the effects of NB-DGJ on glycosphingolipid metabolism during embryonic and postnatal brain development. NB-DGJ (N-butyldeoxygalactonojirimycin) is a water-soluble inhibitor of the ceramide specific glucosyltransferase, a key enzyme for glycosphingolipid (GSL) biosynthesis. Preliminary findings indicate that NB-DGJ can inhibit GSL biosynthesis without altering viability or morphogenesis in the organogenesis stage cultured whole mouse embryo. Moreover, our collaborators showed that a structural isomer of NB-DGJ could prevent lysosomal storage in adult Tay-Sachs mice and could reduce neurological abnormalities in juvenile Sandhoff disease mice. There have been no prior studies on the effects of NB-DGJ on the GSL composition and morphogenesis in the mammalian embryo growing in utero or during early postnatal brain development. This research will examine for the first time: 1) the effects of NB-DGJ on the GSL composition of embryonic and postnatal brains in mouse models of the gangliosidoses, 2) the influence of NB-DGJ treatment on embryonic and postnatal brain development, and 3) whether embryonic and postnatal NB-DGJ treatment has long-lasting effects on brain development, neurochemistry, and behavior. The content and distribution of GSLs will be measured in neural and nonneural tissues of control and NB-DNJ-treated mice. Embryonic and postnatal brain development will be assessed from morphological, histological, and biochemical measurements. Since there are no effective treatments for human ganglioside storages disease, the proposed research could offer a novel therapy for the early intervention of these neurodegenerative disorders.